Various imaging techniques including magnetic resonance imaging (MRI), computed tomography, positron emission tomography, and optical microscopy in the bio-imaging fields have been employed for disease and other diagnosis. Among these imaging methods, MRI is known as a powerful medical diagnostic technique due to its inherent advantages such as non-invasiveness, safety, and high spatial resolution. It can differentiate abnormalities from normal tissues based on their varied NMR water proton signals arising from different water densities and/or nuclear relaxation rates. Compounds of highly paramagnetic metal ions, such as Gd3+ and Mn2+ are often administered to facilitate a more accurate diagnosis by enhancing the contrast between tissues by increasing water proton relaxation rates. Because Gd3+ has high electron spin (S=7/2) and low electronic relaxation, Gd-based compounds, in particular Gd-DTPA (DTPA=diethylene triamine pentaacetic acid) have been clinically used as MRI positive contrast agents. However, the use of MRI agents of the Gd-DTPA type is limited due to their only moderate longitudinal (r1) relaxation rates and a required large administration dose (several grams per patient). The latter is a serious concern for patients with severe kidney failure.
In this regard, metal-organic frameworks (MOFs) have recently emerged as MRI contrast agents and received increased attention as they allow for three-dimensional images with high spatial resolution (Della Rocca, J., Lin, W., Nanoscale metal-organic frameworks: magnetic resonance imaging contrast agents and beyond, Eur. J. Inorg. Chem. 24(2010) 3725-3734, Della Rocca, J. et al., Nanoscale metal-organic frameworks for biomedical imaging and drug delivery, Acc. Chem. Res. 44(2011) 957-968, Horcajada, P. et al., Metal-organic frameworks in biomedicine, Chem. Rev. 112(2012) 1232-1268, Wang, C. et al., Metal-organic frameworks as a tunable platform for designing functional molecular materials, J. Am. Chem. Soc. 135(2013) 13222-13234, Liu, D. et al., Metal-organic frameworks as sensory materials and imaging agents, Inorg. Chem. 53(2014) 1916-1924).
MOFs are a class of hybrid materials composed of metal ions connected by a variety of organic ligands through non-covalent bonds. They have shown high potential applicability in diverse fields, such as gas adsorption, storage and separation, nonlinear optics, catalysis, and biomedical applications. As MRI agents, MOFs have many advantages, in particular in carrying large amounts of paramagnetic metal ions. For example, Gd3+ and Mn2+ containing MOFs have shown excellent efficacy as T1-weighted contrast agents with large per metal- and particle-based MRI relaxivity (Chen, S. H. et al., Development of a Gd (III)-based receptor-induced magnetization enhancement (RIME) contrast agent for δ-glucuronidase activity profiling, Inorg. Chem. 51(2012) 12426-12435, Molnar, E. et al., Picolinate-containing macrocyclic Mn2+ complexes as potential MRI contrast agents, Inorg. Chem. 53(2014) 5136-5149). Recently, it is reported that Mn2+ centers in MOFs exhibit very high in vivo r1 MRI relaxivities by binding to intracellular proteins.
For future clinical application, moisture stability and water solubility are important prerequisites for MOFs to function in the basic in vivo environment. However, low moisture stability and water insolubility of many MOFs significantly limit their application (Greathouse, J. A., Allendorf, M. D., The interaction of water with MOF-5 simulated by molecular dynamics, J. Am. Chem. Soc. 128(2006) 10678-10679). Moreover, the cytotoxicity of some MOF backbones is an issue further limiting its theoretical clinical use (Kundu, T. et al., Mechanical downsizing of a gadolinium(III)-based metal-organic framework for anticancer drug delivery, Chemistry 20(2014) 10514-10518).
Accordingly, there remains a strong need for economic and cost-efficient manufacturing processes and obtainable compounds suitable as contrast agents for magnetic resonance imaging with sufficiently high longitudinal (r1) relaxation rates under the administration of acceptable doses. Such compounds shall possess low cytotoxicity and need to have an appropriate moisture stability and water solubility as prerequisite for the in vivo utilization.